PROJECT SUMMARY/ABSTRACT Type 2 diabetes mellitus (T2D) is common and results in enormous personal and societal costs. While many complications of T2D are well-established, less is known about the link between T2D and the brain, beyond associations with cerebrovascular disease, cognitive impairment, and dementia. Recent data show that insulin resistance (InsRes), a key component in T2D, may be present in the aging human brain itself and be associated with Alzheimer?s disease (AD) pathology, including amyloid-?, and cognitive impairment. A pressing scientific question is whether peripheral (systemic) InsRes is related to central (brain) InsRes and to AD. In response to PAR-17-031 calling for studies to elucidate metabolic regulation, and insulin signaling in particular, in AD, we propose an interdisciplinary project with the overall goal to examine associations of peripheral with central insulin resistance, and the associations of peripheral and central insulin resistance with AD neuropathology and cognitive function. The proposed study will take advantage of available biospecimens (frozen ante-mortem serum and peripheral blood mononuclear cells, and postmortem skeletal muscle and brain tissues) from which to quantify markers of chronic hyperglycemia and InsRes, and from which to use existing laboratory, clinical, and neuropathologic data, from 200 community-dwelling women and men, with and without T2D, who were well-characterized clinically and died and came to autopsy (R01AG17917). First, we will characterize peripheral (blood, muscle) and central (brain) InsRes in biospecimens, using two complementary approaches, including biochemical assays and an ex vivo stimulation paradigm to directly examine the insulin receptor signaling cascade (Aims 1 and 2). Next, we will test the hypothesis that peripheral InsRes is linked to central InsRes, and conduct additional analyses considering secondary markers of interest and whether other factors, such as sex and others, affect associations (Aim 3). Finally, in a translational aim, we will test the hypotheses that peripheral and central InsRes are associated with neurodegenerative and cerebrovascular neuropathology, and domain-specific cognitive function (Aim 4). Because InsRes is a key component of T2D for which therapies are available, this study which will test the link of peripheral and central InsRes, and neuropathology and cognition in persons with and without T2D, will fill major gaps in scientific knowledge and inform future research in the field of metabolism, insulin signaling, and AD, and provide important data with potential to improve public health.